Treatment of human herpesviruses using hyperthermia

ABSTRACT

The invention provides a method of treating a patient infected with a human herpesvirus comprising raising the core temperature of the patient and then returning the core temperature of the patient to normal at least one time, wherein the core temperature is raised to a temperature range and a duration sufficient to reduce or eliminate the patient&#39;s viral load of the human herpesvirus.

FIELD OF THE INVENTION

This invention relates to hyperthermic treatment of herpesviruses.

BACKGROUND OF THE INVENTION

Human herpesviruses cause many diseases such as chicken pox.Epstein-Barr virus, human cytomegalovirus, varicella-zoster virus,herpes simplex virus-1, or herpes simplex virus-2 are examples of humanherpesviruses. Recent studies have identified human herpesvirus-8(HHV-8) as the putative agent causing Kaposi's sarcoma (KS).

In order to infect tissues and cell of the body, viruses have developedmany different ways to evade or deceive the immune system. The humanherpesviruses use latency as a defense against the immune system.Latency is the ability to be inactive when conditions are not right forproliferation or growth. A key to defeating these viruses is to forcethem into an active proliferation at a time when conditions are wrong.

Current treatments for human herpesviruses include aciclovir, cidofovir,famciclovir, doxorubicin and other pharmaceuticals. However, becausethese treatments are not effective for all patients, improved methodsfor treating human herpesviruses are being sought.

SUMMARY OF THE INVENTION

The invention provides a method for treating a patient infected with ahuman herpesvirus comprising raising the core temperature of the patientand then returning the core temperature of the patient to normal atleast one time. The core temperature is raised to a temperature range, aduration, and a number of times sufficient to reduce or eliminate thepatient's viral load of the human herpesvirus.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary and explanatory and areintended to provide further explanation of the invention as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a simplified perspective view of an apparatus used to practicethe invention.

FIG. 2 is a mechanical diagram showing cannulation sites on a humanadult.

FIG. 3 is a simplified diagram of the system illustrated in FIG. 2.

FIG. 4 is a cross-section of a temperature sensor.

FIG. 5 is a cross-section of a temperature catheter having a temperaturesensor positioned at the urinary sphincter muscle with the aid of aninflatable cuff that engages the bladder wall.

FIG. 6 is a cross-section of temperature catheter having two temperaturesensors, one of which is positioned at the urinary sphincter muscle withthe aid of an inflatable cuff the engages the bladder wall and thesecond of which is positioned in the urine pool.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a method for treating a patient infected with ahuman herpesvirus comprising raising the core temperature of the patientand then returning the core temperature of the patient to normal atleast one time. The core temperature is raised to a temperature range, aduration, and a number of times sufficient to reduce or eliminate thepatient's viral load of the human herpesvirus. “Treating” in thisapplication means raising the core temperature to a temperature range, aduration, and a number to times sufficient to reduce or eliminate thepatient's viral load of the human herpesvirus. Raising the coretemperature upregulates the human herpesvirus. At the high temperaturesencountered with hyperthermia, and the up-regulation of the immunesystem (granulocytosis etc.) the human herpesviruses are dispersed intoa hostile environment where antibody and cell mediated responses canoccur. Pharmaceutical administration prior to, during, or after thistime frame could be devastating to the various herpes species activated.

“Returning the core temperature of the patient to normal” includesallowing the patient to cool through ambient heat loss and activelycooling the patient. In the examples described below, the patient iscooled by ambient heat loss and active cooling to a temperature of 39°C. The patient is released from the hospital and the patient'stemperature gradually returns to normal (37° C.) over a period of a fewdays. In one embodiment, the core temperature of the patient is raisedand returned to normal one time. In another embodiment, the coretemperature of the patient is raised and returned to normal two or moretimes. In one embodiment, the core temperature is raised by circulatingthe patient's blood from the patient, through an extracorporeal bloodflow circuit, and back to the patient, wherein the blood returned to thepatient has been heated within the blood flow circuit to an elevatedtemperature range. The patient's blood can be circulated from thepatient through a blood vessel and returned to the patient through ablood vessel. In one embodiment, the patient's blood is circulated fromthe patient through a vein and returned to the patient through a vein.In another embodiment, the patient's blood is circulated from thepatient through an artery and returned to the patient through a vein. Inanother embodiment, the core temperature is raised by inserting aheating element into the patient and the heating element heats thepatient's blood. The heating element can be inserted into a blood vesselof the patient.

The heating element can be inserted into a central vessel, i.e., aortaor vena cava, where it can heat the blood passing by and eventuallyheating the blood to such a degree that the net temperature gain exceedsthe losses due to the normal (physiologic) cooling mechanisms. Over timethe body temperature can be raised to a predetermined point andmaintained for a predetermined time. The heating element can be housedwithin a sheath or catheter at one or multiple positions along itslength. The sheath or catheter can contain wires, conduits, fiberoptic,or other materials to supply power to the heating element. External tothe body there could be a plug to connect the sheath or catheter to thecontrol system. The sheath or catheter can be treated to give itantithrombogenic properties. This treatment can be chemical or a highenergy corona or plasma discharge in the presence of a monomeric gas.The method of insertion can be through a cut-down or percutaneously(Seldinger Technique).

The heating element's method of heating can be by an electrical heating,radiofrequency, laser, or small coils through which hot solution can becirculated. The heating element should not exceed 50° C. at the surfacethat contacts blood.

Such a heating element can be used for core heating and can also be usedfor local or regional heating. For example, a percutaneous insertioninto an artery with a hollow sheath or catheter can be made toaccommodate a steering guidewire so the device can be placed into thehepatic artery. A second hollow catheter with a thermistor tip can beplaced, via a venous percutaneous stick, into the hepatic vein for livertemperature.

Methods which heat the blood to raise the core temperature, such asextracorporeal whole body hyperthermia, are preferred. However, methodsin which the core temperature is raised by other methods such as byinfrared radiation, convection, or surface contact such as a heatingblanket can also be used in the method of the invention.

The core temperature can be raised to a temperature range of from 38 to48° C., more preferably 38 to 44° C., more preferably 41.8 to 42.2° C.The core temperature can be raised for a period of from 2 minutes tosixteen hours, a period of from one-half to three hours, a period offrom one to two hours, a period of from 80 to 100 minutes, or for 90minutes. The core temperature can be taken rectally. For purposes ofthis application, the “core temperature” means rectal temperature.Temperatures other than the rectal temperature can be taken in thepractice of the invention, e.g., esphogeal, bladder, tympanic, orcardiac line temperatures. The relationship between such othertemperatures and the rectal temperature is well known in the art andsuch measurement by other methods will allow determination of the coretemperature as defined herein.

Recommended exposure times during extracorporeal whole body hyperthermiaare given in Table 1 below.

TABLE 1 Core Temperature (° C.) Exposure (minutes) 39 960 40 480 41 24042 120 43 60 44 30 45 15 46 8 47 4 48 2

The patient's viral load of the herpesvirus can be determined at leastonce before the core temperature has been raised at least one time; atleast once after the core temperature has been raised and returned tonormal at least one time; at least two different times after the coretemperature has been raised and returned to normal at least one time, orcombinations thereof.

In embodiments of the invention, the patient's viral load of the humanherpesvirus is reduced by 30 percent or more one month after the coretemperature has been raised and returned to normal at least one time,more preferably, by 50 percent or more, by 75 percent or more, by 90percent or more, or by 95 percent or more. In a preferred embodiment,the patient's viral load of the human herpesvirus is reduced to lessthan the sensitivity level of a branched DNA signal amplification testone month after the core temperature has been raised and returned tonormal at least one time. This determination of the patient's viral loadis made one month after the last of the hyperthermic treatments. Inanother preferred embodiment, the patient's viral load of the humanherpesvirus is reduced to less than the sensitivity level of a reversetranscriptase-polymerase chain reaction test one month after the coretemperature has been raised and returned to normal at least one time.

In embodiments of the invention, the patient's viral load of the humanherpesvirus is reduced by 30 percent or more three months after the coretemperature has been raised and returned to normal at least one time,more preferably, by 50 percent or more, by 75 percent or more, by 90percent or more, or by 95 percent or more. In a preferred embodiment,the patient's viral load of the human herpesvirus is reduced to lessthan the sensitivity level of such branched DNA signal amplificationtest three months after the core temperature has been raised andreturned to normal at least one time. In another preferred embodiment,the patient's viral load of the human herpesvirus is reduced to lessthan the sensitivity level of such reverse transcriptase-polymerasechain reaction test three months after the core temperature has beenraised and returned to normal at least one time.

The method of the invention can further comprise treating the patientwith a pharmaceutical indicated for the human herpesvirus. The efficacyof a pharmaceutical effective for treatment of the human herpesvirus insome patients can be increased when combined with hyperthermia. Themethod of the invention can also comprise treating the patient with apharmaceutical indicated for the human herpesvirus where suchpharmaceutical was not efficacious for stand alone treatment for thehuman herpesvirus and when combined with hyperthermic treatment resultsin the pharmaceutical being efficacious in some patients. The patientcan be treated with a single pharmaceutical effective against the humanherpesvirus or with two or more pharmaceuticals effective against thehuman herpesvirus. The drug can be administered to the same patient atseveral points: before raising the core temperature of the patient atleast one time, while the core temperature of the patient is raised, andafter the core temperature of the patient has been raised and returnedto normal at least one time, or combinations thereof.

The pharmaceutical can be selected from interferons, proteaseinhibitors, cytokines, chemotherapeutic agents, or any combinationthereof. The pharmaceutical can be selected from ribavirin, lamivudine,interferon alfacon-1, interferon alfa-2a, interferon alfa-2b,interferon-alfa-n1, thymosin alpha-1, interleukin-2, interferonalpha-n3, ketoprofen, interferon beta-1a, interferon gamma-1b,interleukin-12, histamine dihydrochloride, thymalfasin, zidovudine,didanosine, zalcitabine, stavudine, abacavar, nevirapine, delaviridine,efavirenz, ritonavir, indinavir, nelfinavir, saquinavir, amprenavir,doxorubicin, aciclovir, cidofovir, famciclovir, foscamet, ganciclovir,idoxuridine, trifluorothymidine, valaciclovir, vidarabine, orcombinations thereof. In a preferred embodiment, the pharmaceutical canbe selected from an interferon, ribavirin, lamivudine, or doxorubicin.In another preferred embodiment, the pharmaceutical is an alphainterferon. In yet another preferred embodiment the pharmaceutical isdoxorubicin, more preferably liposomal doxorubicin. The pharmaceuticalcan also include antioxidants, non-steroidal anti-inflammatory drugs,and/or reactive oxygen free radical scavengers. Several pharmaceuticalsare being studied and some are available for treatment of humanherpesviruses. Doxorubicin is one pharmaceutical used for the treatmentof Kaposi's sarcoma.

In a preferred embodiment, the human herpesvirus is selected from humanherpes virus-8, Epstein-Barr virus, cytomegalovirus, varicella-zostervirus, herpes simplex virus-1, herpes simplex virus-2, human herpesvirus-6, or human herpes virus-7; in other preferred embodiments, thehuman herpesvirus is each of these viruses. In another embodiment, thehuman herpesvirus is not human herpes virus-8. In another preferredembodiment, the herpesvirus is HHV-8, the patient has been receivingdoxorubicin, and the patient still has progressive Kaposi's sarcomaprior to the treating.

The patient infected with the herpesvirus might have an acuteherpesvirus infection or a latent herpesvirus infection. The patientmight be co-infected with a pathogen. The pathogen might be a virus, aspirochete, or a bacterium. The pathogen might be a heat labile virus.The heat labile virus might be selected from hepadnaviruses,togaviruses, flaviviruses, coronaviruses, rhabdoviruses, filoviruses,paramyxoviruses, othomyxoviruses, bunyaviruses, arenaviruses, orretroviruses. The heat labile virus might be HIV, hepatitis B virus, orhepatitis C virus. In a preferred embodiment, the heat labile virus isHIV. The spirochete might be from the genus treponema, borrelia, orleptospira. The spirochete might be Treponema pallidum, Treponemapertenue, Treponema carateum, Treponema pallidum endemicum, Borreliaburgdorferi, Borrelia hermsii, or Leptospira interrogans. The bacteriummight be an aerobic or anaerobic bacterium.

Conventional hyperthermia equipment can be used in the methods of theinvention.

A number of different tests are used to determine if a person has beeninfected with a herpesvirus. Clinicians will also test specifically fora herpesvirus. One set of tests looks for the presence of antibodies tothe herpesvirus. If the antibodies are present in a person's blood, itusually means that the person has been infected with the herpesvirus.

Other tests that are frequently performed detect the presence ofherpesvirus DNA. Tests that are used to measure herpesvirus DNA includenucleic acid amplification diagnostic tests.

EXAMPLES

A thirty-eight year old HIV/AIDS patient who was failing HIVpharmaceutical therapies was treated. The patient received a singlesession of Extracorporeal Whole Body Hyperthermia (EWBH). The patientcontinued his HIV drug regimens until the start of the hyperthermiatreatment and discontinued his drug regimens for the treatment andfollow-up period.

The patient was failing pharmaceutical therapy, as defined by (A) an HIVPCR viral load ≧10,000 on a stable antiviral regimen, and (B) thefailure of two or more combination antiviral regimens composed of allthree of the following categories: two nucleoside analogues, onenon-nucleoside reverse transcriptase inhibitor and one proteaseinhibitor. The patient underwent a single hyperthermic treatment inwhich his core body temperature was raised to a maximum of 41.8±0.2° C.for 90 minutes.

The patient was diagnosed with HIV in 8/88 and KS 12/95. While receivingtreatment with cryotherapy and intralesional vinblastine, he developed15 new KS lesions in 3/98 while experiencing virologic failure of aPI-containing 4-drug regimen. Liposomal doxorubicin infusionsadministered every 3 to 6 weeks for 18 months achieved remission of theKS. He had experienced virologic failure of 9 prior HAART regimens andhad an HIV RNA PCR of 305,700 while taking a 6-drug regimen when hedeveloped 4 new lesions. His CD4% and cell count dropped from 24/236 to5/26 over 10 months, and his viral load was 317,214 (log 5.50) at ascreening baseline. He discontinued HAART and underwent a single sessionof EWBH. Five weeks following EWBH, he received one dose of liposomaldoxorubicin. At week 8, all four active lesions had achieved partialremission, and prior treated lesions were lightening. Off HAART, at week8, viral load was 235,837 (log 5.37), CD4% and cell count 8/13 (WBC's0.9 following doxorubicin).

The results of the EWBH treatment of the patient are presented below inTable 2.

TABLE 2 TREATED PATIENT DATA Interval HIV Viral Patient Date Load CD4CD4% CD8 CD8% Bilirubin Platelets ALT AST Patient 1 Baseline 0 104,92222 5 290 66 0.4 124,000 31 24 Day 1 1 745,156 12 12 41 41 1.0 39,000 139241 Day 3-7 10 86,309 22 3 533 73 0.9 253,000 79 34 Month 1 27 116,02314 6 146 61 1.2 108,000 45 34 Month 2 60 235,837 13 8 112 64 2.9 191,00055 48 Unsch 95 322,916 11 4 114 45 0.6 152,000 122 90

Table 2 provides the HIV viral load (copies/mL), CD4 lymphocytes count(cells/mm³), CD4%, CD8 lymphocytes count (cells/mm³), CD8%, bilirubin(mg/dL), platelets count (cells/mm³), ALT (UAL), and AST (U/L).

According to the preferred embodiment, the patient will be screened forsubsequent hyperthermic treatment as follows. The patient will befollowed until he experiences a confirmed 0.5 log or greater increase inHIV viral load either (1) from baseline, if no decline in viral load isachieved after receiving EWBH, or (2) from the lowest recorded HIV viralload following EWBH. In the event the patient experiences a confirmed0.5 log or greater increase in HIV viral load, he will be re-screenedfor eligibility of EWBH, and if eligible, will be offered another singlesession of EWBH and followed per protocol. The criteria for re-treatmentwill be a 0.5 log increase in HIV viral load above baseline or nadir,whichever is greater. The details of the clinical protocol followed forthe patient and the equipment used are presented below.

Clinical Protocol

The purpose of this investigation was to assess the efficacy of a singleEWBH treatment in individuals who were failing pharmaceutical therapiesfor HIV. Failing pharmaceutical therapies is defined as (A) an increasein HIV PCR viral load to ≧10,000 while on a stable antiviral regimen,and (B) the failure any two combination antiviral regimens composed ofall three of the following categories: two nucleoside analogues, onenon-nucleoside reverse transcriptase inhibitor and one proteaseinhibitor. A stable antiviral regimen is defined as no changes inantiretroviral regimen for sixteen weeks prior to screening for thestudy. Antiviral regimens will usually give peak PCR lowering within 8to 16 weeks after initiation.

In the event a patient experiences a confirmed 0.5 log or greaterincrease in viral load from baseline or nadir, they will be re-screenedfor eligibility for EWBH, and if eligible, will be offered anothersingle session of EWBH and followed per protocol. All patients will haveblood work drawn and analyzed at screening, during treatment, and atfollow-up as per protocol. The criteria for re-treatment will be a 0.5log increase in viral load above baseline or nadir, whichever isgreater.

Analysis of primary objective parameters included HIV viral loading asmeasured by Polymerase Chain Reaction (PCR), HIV-RNA, and CD4 cellcounts and percentages. Secondary objective parameters included theassessment of the cumulative incidence of opportunistic infections inthe EWBH treated verses the control populations. Clinical utility, dataassessing quality of life, were followed to evaluate significance ofthis treatment, pre and post therapy.

Prophylactic medication was allowed during the protocol period andappropriate treatment was given for opportunistic infections.Prophylactic medication to minimize the risk for recurrent Herpesinfection was allowed. Any HIV/AIDS physical lesions present prior totherapy was measured and, if possible, photographed so that theselesions can be followed post treatment.

Patients fulfilled the following criteria to be eligible and had noineligibility exclusions:

1. Documentation of positive test for Human Immunodeficiency Virus(HIV-1) Enzyme Linked Immunosorbent Assay (ELISA), confirmed by WesternBlot.

2. Were failing recommended pharmaceutical therapy as defined by (A) anHIV PCR viral load of ≧10,000 while on a stable antiviral regimen(defined as no changes in antiretroviral regimen for sixteen weeks priorto screening for the study), (B) the failure of at least two combinationantiviral regimens composed of 2 or more antiretroviral medications, and(C) prior use of at least two nucleoside analogues, one non-nucleosidereverse transcriptase inhibitor, and one protease inhibitor.

4. Karnofsky Performance status: ≧70%.

5. Male or female, age 18-60 years old, inclusive.

6. Granulocyte ≧500/mm³; White Blood Count (WBC) ≧1500/mm³; plateletcount ≧100,000/mm³; hematocrit ≧30 vol %, and hemoglobin ≧10 g/dl.

7. Prothrombin Time (PT), Activated Partial Thromboplastin Time (aPTT),antithrombin III, fibrinogen, and thrombin time ≦20% of upper or lowerlimits of normal range.

8. Serum creatinine <2.0 mg/dL.

9. Serum aspartate aminotransferase (SGOT, AST) and Serum alanineaminotransferase (SGPT, ALT) ≦5×upper limit of normal.

10. Negative pregnancy test for females.

11. CD4+lymphocyte helper cells ≦500 cells/mm³.

12. Roche Amplicor HIV-1 RNA PCR ≧10,000 copies/ml.

13. Signed informed consent.

14. Stress Echocardiogram, or stress test and echocardiogram, orechocardiogram nucleotide studies with EF ≧45%, normal LV function andno evidence of coronary artery disease.

15. Forced Expiratory Volume (FEV1) ≧60% of expected function.

16. Negative CT scan of the brain with contrast.

17. Willingness to adhere to follow-up schedule.

Patients that exhibited any of the following were excluded from theprotocol:

1. New York Heart Association (NYHA) classification III or IV.

2. History of a myocardial infarction, abnormal stress test suggestingischemic changes, malignant, uncontrollable arrhythmia's or documentedunstable angina within the last 12 months.

3. Major surgery within four weeks of protocol therapy.

4. History of central nervous system hemorrhage attributable to bleedingdiathesis, or previously documented cerebrovascular accident.

5. Evidence of any active opportunistic infection. Patient must be atleast four weeks status post therapy for opportunistic infection.

6. Allergic history to heparin, protamine, pork/beef products, fish,lidocaine or other anesthetic agents.

7. Uncontrolled hypertension, systolic BP 160 and diastolic BP 105.

8. Active illicit drug use determined by history.

9. Currently enrolled in other investigational clinical trial that wouldpreclude participation in this protocol.

In the preferred embodiment, patients receiving EWBH treatment wouldcontinue their current drug regimens until EWBH treatment and thendiscontinue their drug regimens for the treatment and follow-up period.All EWBH-treated patients were be followed until they experienced aconfirmed 0.5 log or greater increase in viral load either (1) frombaseline, if no significant decline in viral load was achieved afterreceiving EWBH, or (2) from the lowest recorded viral load followingEWBH. In the event an EWBH patient experienced a confirmed 0.5 log orgreater increase in viral load from baseline or nadir, they werere-screened for eligibility of EWBH, and if eligible, were offeredanother single session of EWBH and followed per protocol. All patientswere followed per protocol with serial collection of subjective andobjective data. All data was accumulated, tabulated and analyzed.

For purposes of analysis, all patients (EWBH and Control) remained onstudy until: (1) criteria for treatment is documented (≧0.5 log increasein PCR from baseline or nadir); (2) end of the six-month follow-upfollowing initial randomization; or (3) loss to follow-up, withdrawal,or death during six-month follow-up.

Analysis of primary objective parameters included HIV viral load asmeasured by Roche Amplicor HIV-RNA PCR, available from RocheDiagnostics, Nutley, N.J., lymphocyte subset profile and percentages(CD4). Secondary objective parameters included the assessment of thecumulative incidence of opportunistic infections in the patients.Clinical utility, data assessing quality of life were followed toevaluate significance of this treatment, pre and post therapy. Theobserved risks (i.e., device-related and treatment related adverseevents) of EWBH were monitored in relation to the potential benefits ofthe therapy.

Each patient was informed of all procedures to insure that there wouldbe compliance with the visits required for treatment and for thefollow-up process. Patients received the best available care for medicalproblems arising during the study. Current medications were noted at thetime of screening and reported on the case report form. Drugsadministered or taken during the trial were recorded on the case reportform, specifying the type of medication, dose, schedule, duration andreason for its use. All hospital admissions, clinic/office visits,incidence of opportunistic infections, including treatment given andduration, were closely monitored and recorded on Serious Adverse Event(SAE) and Adverse Event (AE) forms.

Clinical history included the date of HIV/AIDS diagnosis, history ofsymptoms (dates and severity), and therapies previously administered,with duration of use and reasons for discontinuation. The historyincluded all known allergies.

Clinical assessment included blood studies as listed in Table ofRequired Observations. Follow-up bloods were obtained at Day 1 post EWBHtherapy and were repeated at follow-up clinic visits at day 3-7, months1, 2, 4, and 6 months (±1 week) (to the extent that the patient hadreached these time points).

The following studies were performed in addition to the physicalexamination. Pre-procedure blood sampling was obtained on the morning ofadmission. Additional tests were repeated throughout the study (seeTable of Required Observations). Tests and procedures were repeated asnecessary to assess clinical toxicity.

1. Hematology:

Complete Blood Count (CBC, including WBC) with differential

Blood type (ABO Rh)

2. Coagulation:

Prothrombin time (PT), Partial thromboplastin time (aPTT), AntithrombinIII, Thrombin time, Fibrinogen

3. General chemistries:

Sodium, Potassium, Chloride, CO₂, Calcium, Phosphorous, Magnesium,Glucose, Albumin, Creatinine, Cholesterol, Total protein, ALT, AST,Total bilirubin, Alkaline phosphatase, Creatinine Phosphokinase (CPK),Lactate Dehydrogenase (LDH), Blood Urea Nitrogen (BUN),

4. Cardiac assessment:

Stress Echocardiogram with Electrocardiogram (EKG)

5. Pulmonary assessment:

Chest X-ray (CXR), Pulmonary Function Tests (1 Second Forced ExpiratoryVolume, FEV1, and Forced Vital Capacity, FVC)

6. Renal Function:

BUN, Creatine

7. Neurologic assessment:

Thorough neurological physical examination

Computed Axial Tomography (CAT) scan with contrast of the head

8. Immune system assessment:

Lymphocyte phenotype profile, including CD4, and CD8.

HIV RNA PCR (Roche Amplicor).

9. Chronic Hepatitis assessment:

Hep C Qual. PCR

Hep B Surface antigen

HepB DNA PCR (if HBSAg positive)

10. Measurement and documentation of any lesions, if appropriate byphotographs.

11. Measure of overall Kamofsky performance status

TABLE OF REQUIRED OBSERVATIONS Days^(1,2) Months^(1,2) Test/ProcedureSCREEN^(1,2) 0 1 3 1 2 4 6 Consent Form(s) X ELISA/Western Blot X HIVRNA PCR level X X X X X X X X CD4/CD8 level X X X X X X X X HepC Qual.PCR X X** X** Hep C bDNA (Bayer) X*** X*** X*** X*** X*** X*** X*** X***Hep BSAg X HepB DNA PCR**** X X X X X X X X HIV Genotype X X History andPhysical X X X X X X X X CXR X Hematology X X X X X X X X Blood Type XCoagulation X X X X X X X X Biochemical Profile X X X X X X X X CardiacAssessment X Pulmonary Assessment X Urine Analysis & Culture XNeurologic Assessment X Karnofsky Status X X X X X X X Lymph NodeBiopsy³ X X X X Spinal Fluid Specimen⁴ X X X X Health StatusQuestionnaire X X X X X X *Any test, measurement, or assessment wasperformed at any time, as clinically indicated. **If HCV Qualitative PCRis negative ***If HepC Qualitative PCR is positive ****If HBSAg ispositive at screening ¹EWBH treatment group ²Control group ³Lymph Nodebiopsies were performed on the patients 1 to 7 days prior to the EWBHtreatment, at day 1, day 3-7, and Month 6 or prior to re-treatment withEWBH (to the extent the patient had reached these time points). ⁴Lumbarpuncture was performed to obtain spinal fluid from the EWBH treatedpatients 1 to 7 days prior to the EWBH treatment, at day 1, day 3-7, andMonth 6 or prior to re-treatment with EWBH (to the extent the patienthad reached these time points). Health Status Questionnaire wascompleted @ screening, Day 3, and months 1, 2, 4, 6.

The following protocol design was used in the hyperthermic treatmentarm.

A. Pre Procedure

After the history, physical examination, and laboratory procedures hadbeen completed, and entry criteria satisfied, the patient was admittedto the hospital on the day of the procedure. Bloods were drawn accordingto the Table of Required Observations. Patient was Nothing Per Os (NPO)for at least 6 hours prior to the procedure. Preoperative antibioticswere given prophylactically for 24 hours.

Procedural Parameters

Once in the Operating Room (OR) or treatment room s/he was placed on theOR table and prepared for the procedure.

1. Description of Treatment Facility:

The OR or treatment room used for the procedure DID not have to bemodified for this procedure. The operating table was equipped with afoam rubber mattress and/or pads for flexor point protection.

2. Patient Instrumentation for EWBH:

The following was placed in the operating room prior to EWBH:

i. Swan-Ganz EKG lead monitoring

ii. Peripheral intravenous (IV) lines (2),

iii. Radial artery catheter

iv. Pulmonary artery (Swan-Ganz type) thermistor catheter via centralvein.

v. Oximeter.

vi. Urinary bladder catheter with thermistor.

vii. Rectal temperature probe.

viii Esophageal temperature probe (general anesthesia).

ix Tympanic temperature.

x. Bilateral femoral venous catheters was placed by a surgeon andconnected to the hyperthermia unit

Temperature probes (esophageal, rectal, and tympanic) were calibrated,within 0.1° C., to a NIST traceable device.

3. Anesthesia:

Anesthetic management was the responsibility of the anesthesiologistadministered appropriate agents according to the standard of care. Thechoice of anesthetic agent was determined based on individual patientprofile. Either general anesthesia or sedative agents can be used.

To ensure an adequate hourly urine volume, a dopamine drip at 2-3mcg/kg/min was used throughout the procedure and in the earlypostoperative period. Average urinary flow of 30 cc/hr minimum wastargeted. Fluid replacement during the procedure was administered at thediscretion of the operating team. Albumin and mannitol were not usedduring the hyperthermia treatment.

4. EWBH conduct, all parameters were entered on case report forms:

From the Swan Ganz catheter, serial readings of pulmonary systolic anddiastolic pressures and blood temperature were recorded.

Cardiac output (CO) as measured via the thermodilution catheter wasmeasured prior to and following the treatment.

Each patient was continuously monitored at 5 minute intervals fortemperature during the procedure. The perfusionist recorded allperfusion data on specific perfusion data forms. Other patientparameters were recorded on standard OR flow sheets.

Temperatures Monitored

Rectal (T_(R)), Esophageal(T_(E)), Tympanic (T_(P)), Pulmonary Artery(T_(PA)), Water Inlet/Heat Exchanger (T_(W)), Blood Outlet/HeatExchanger (T_(Bld))

a. Preparation:

The perfusionist primed the circuit with an isotonic solution, andcirculated until totally de-aired. The surgeon cannulated the femoralveins using open or percutaneous methods for connection with theextracorporeal circuit.

A predetermined dose of heparin required for extracorporeal circulatorybypass was calculated at 150 units/kg and administered in two 75 unit/kgdoses with an Activated Clotting Time (ACT) determination before andafter each dose. An ACT 2-½ to 3 times normal was maintained duringEWBH. Further doses of heparin, if needed, were administered accordingto ACT measurement.

b. Heating Phase:

The time to reach a core temperature of 41.8°±0.2 was about 40 minutes.

i. EWBH was initiated at a blood flow rate of approximately <20% of thebaseline cardiac output. The water circulating through the heatexchanger did not exceed 50° C. for longer than 5 minutes.

ii. When either T_(E) or T_(R) (whichever is greater) reached 41.8°±0.2°C., the plateau phase was begun.

iii. When 40.0° C. is reached, ice packs were placed under and/or aroundthe patient's neck.

c. Plateau Phase:

i. Core body temperature (T_(E), or T_(R), whichever is greater) wasmaintained between 41.6-42.0° C. for 90 minutes. TW was reduced so thatneither T_(E) or T_(R) exceeded 42.0° C. Since body temperature cannotbe instantaneously changed, momentary excursions above 42.0° C. were notbe considered protocol deviations.

ii. Blood flow was altered to regulate blood and core temperature.

d. Cooling Phase:

Anticipated time to reach 39° C. is 30-45 minutes.

i. Cooling was initiated at first by discontinuing the water flow forthe first 20 minutes, cooling by ambient heat loss.

ii. After 20 minutes the thermostat was reset to 30° C., and the waterflow re-instituted.

iii. When TR reached 39° C., bypass was discontinued.

iv. Decannulated and reversed heparin with protamine sulfate.

e. Once stable, the patient was transferred to the post anesthesia orrecovery room.

REQUIRED OBSERVATIONS DURING EWBH BY PHASE Warming Plateau Cooling Test*Pre/ 0 15 30 45 0 15 30 45 60 75 90 15 30 Post Blood gases X X X X X X XX X X X X X X Electrolytes X X X X X Biochemistry X X Hematology X XUrine Analysis & Culture X CD4/CD8 X HIV RNA PCRX Hep C bDNA (Bayer)** XHep B DNA PCR*** X HIV-1 Genotype X Coagulation X X ACT only X X X X X XX X X X X X X X X Cardiac output X---------------------------------------------------------- X Urineoutput X ---------------------------------------------------------- XPressure Arterial X---------------------------------------------------------- X Pulmonary X---------------------------------------------------------- X EKG X---------------------------------------------------------- X TemperatureX ---------------------------------------------------------- X CXR XLymph Node BX¹ X Lumbar Puncture² X Legend: X = Discreet sample/monitorpoint X----X = Continuous monitoring recorded at 15 ± 5 minute intervals*Tests may be performed at any time following intervention. **If Hep CQual. PCR is positive at screening ***If Hep B DNA PCR is positive atscreening ¹Lymph node biopsy was performed on the patients 1 to 7 daysprior to the EWBH treatment ²Lumbar puncture for spinal fluid analysiswas performed in the patients prior to the EWBH procedure (1 to 7 daysprior to the EWBH treatment)

C. Post-EWBH Patient Monitoring

1. In the Post Anesthesia or Recovery Room, standard monitoringincluded:

Continuous EKG monitoring

12 lead EKG strip if indicated

Temperature, pulse, respirations and blood pressures (every 15 minutesfor the first one and one-half hours, then every half hour for the nextone and one-half hours),

Urinary output

2. At the time of discharge from the hospital, a CXR was obtained torule out the presence of pulmonary problems such as pneumothorax,atelectasis, etc. Pressure dressing was removed from the femoralcannulation sites to confirm hemostasis.

3. Patients were discharged from the hospital when able to ambulateapproximately 23 hours after admission.

Follow-up Visits

Follow-up visits were required at day 1 between day 3-7, and 1 month (±7days), 2 months (±7 days), 4 months (±7 days), and 6 months (±7 days)after the EWBH treatment (to the extent the patient had reached thesetime points). At follow-up visits the patient was questioned aboutpossible adverse reactions since their last visit, and any reactiondescribed was recorded on the case report form. Blood was drawn forclinical laboratory tests according to the Table of RequiredObservations.

Equipment Used

The contents of the following U.S. patents and patent applications arehereby incorporated by reference into this application: (1) U.S. Pat.No. 5,391,142, issued Feb. 21, 1995, and entitled “Apparatus and Methodfor the Extracorporeal Treatment of the Blood of a Patient Having aMedical Condition,” (2) U.S. Pat. No. 5,674,190, issued Oct. 7, 1997,and entitled “Extracorporeal Whole Body Hyperthermia Using Alpha-StatRegulation of Blood pH and pCO₂,” (3) U.S. patent application No.09/334,224, filed Jun. 16, 1999, entitled “Bladder Catheter forHyperthermia System,” and (4) U.S. patent application No. 09/334,520,filed Jun. 16, 1999, entitled “Thermal Sensor for Hyperthermia System”.

The hyperthermia equipment used was composed of three main components:(a) the console, (b) a heater/cooler unit and (c) the disposable bloodcontact circuit.

The console was composed of an extracorporeal, centrifugal pump deviceused for the operating and monitoring of the hyperthermia procedure. Itcontained the drive motor and controllers for the pump and electronicsfor monitoring the system parameters (temperature, pressure, and flow).The heater/cooler unit was used to raise or lower the patient'stemperature and maintain a desired patient temperature throughconductive heat transfer. Heated water was circulated through the heatexchanger to elevate the patient's temperature. Cool water wascirculated through the heat exchanger to reduce the patient'stemperature.

The disposable blood contact circuit was comprised of components forinducing and monitoring hyperthermia. In order to complete the circuit,vascular access was required. Blood left the patient via a venouscannula and PVC tubing which directed it to a centrifugal pump. From thepump, the blood was propelled through the heat exchanger where thermalexchange occurred, with the assistance of the heater/cooler. After theblood was heated it passed through a blood filter before returning tothe patient via a second venous cannula. Circuit temperature wasmonitored by a calibrated thermistor probe placed within the outlet ofthe heat exchanger. This represented the highest blood temperaturereading in the circuit. The blood temperature and those temperaturesrecorded from the heater/cooler as well as patient temperatures were thebasis of the perfusion management of blood flow and heater/coolertemperature during the procedure.

Circuit flow was measured by an electrically isolated electromagneticflowmeter built into the console, and a flow insert that was located inthe blood circuit. Flow rates values have been determined experimentallyto be approximately <20% of the baseline cardiac output. At these flowlevels the rate of temperature rise to the patient was gradual enoughnot to cause biochemical parameters to change drastically. Blood flowrate adjustment was used with water bath temperature adjustment to finetune the process and maintain the core body temperature within a narrowrange for the appropriate time.

Circuit pressure monitoring was accomplished by the pressure electronicsbuilt into the console and a disposable transducer which was located atthe input side of the heat exchanger. This position within the circuitallowed the operator to monitor resistance to flow downstream of thepump. Changes in the pressure reading were used as a diagnostic tool todetermine circuit integrity and the state of anticoagulation. Aconnection was made between the three-way stopcock, at the transducer,and the two-way stopcock at the pump input. With the three-way stopcockturned to isolate the pump inlet pressure, the operator was able torecognize a possible malposition of the egress cannula. By utilizingthis reading in conjunction with the pulmonary artery diastolic pressureit was possible to anticipate changes in the patient's volume status. A40 μm filter kept blood free of particulate matter.

The system was used to perform hyperthermia treatment of the patient'sblood. The components and sub-assemblies were consolidated andcoordinated to facilitate implementation of use. The apparatus includedstructures which defined an extracorporeal blood flow circuit. Such acircuit included a first cannula for use in cannulating a femoral veinof the patient. Such a cannula defined a blood egress point. A secondcannula was used for cannulating a different femoral vein of thepatient, and the second cannula defined a blood ingress point. Adiscontinuous conduit was provided to interconnect, in part, the firstand second cannulae. A conduit portion of an integrated, sterile modulehad interposed therein a pump, a heat exchanger for regulating thetemperature of blood flowing through the conduit portion, and sensorsfor ascertaining the temperature, pressure, and flow rate of bloodpassing through the conduit portion. The apparatus, further, employed acontroller for regulating the pump and temperature regulators inresponse to temperature, pressure, and blood flow rates sensed by thesensors.

A console was employed with the module having various controls. Suchcontrols were used for selectively changing settings to achieve desiredpressure and blood flow rate through the conduit portion.

The integrated, sterile module was a disposable component. As a result,the medical treatment facility inhibited the possibility ofcontamination of the blood of one patient by HWV positive blood of apatient previously treated, and of health care workers involved in thetreatment.

In cannulating a patient for extracorporeal blood circulation, a bloodflow circuit was defined between a first point of cannulation at a veinof the patient and a second point of cannulation at a vein of thepatient. The patient's blood was then pumped through the circuit. As theblood passed through the circuit, it was heated to a first elevatedtemperature for a relatively short period of time. Thereafter, it washeated to a second elevated temperature, lower than the first elevatedtemperature, for a more extended period of time.

In an embodiment of the invention, the blood is heated to a firstelevated temperature of between 42° C. to 48° C. The blood could,typically, be maintained at the first elevated temperature for a periodof time of about one half to one hour. Thereafter, the blood could bemaintained at the second elevated temperature for a period of about oneto two hours. The second elevated temperature, it is envisioned, couldbe between 42 to 44° C. or 37° C. to 39° C.

Referring now to the drawings wherein like reference numerals denotelike elements through the several views, FIG. 2 shows diagrammaticallythe apparatus 10 used in the hyperthermia treatment of the patients as aprocedure for addressing human herpesvirus infection. In FIG. 2, afemoral vein in the left leg was cannulated as a point of egress ofblood from the patient's body (as at 16), and a femoral vein in thepatient's right leg was cannulated as a point of ingress of the bloodback into the patient (as at 18). It will be understood that these twospecific points of cannulation 16, 18 are not exclusive and that othercannulation locations are specifically contemplated. The locationsillustrated in FIG. 2, however, have been found to be particularlyappropriate, and ingress and egress points in different legs have beenshown as being utilized so that a single leg of the patient is notcompromised.

FIG. 2 illustrates the series blood flow circuit 14 which included firstand second cannulae for cannulating the patient at two veins, aspreviously discussed. A conduit 24 having a discontinuity therein wasprovided to interconnect, in part, the first and second cannulae. Anintegrated, sterile module 26, as best seen in FIG. 1, was interfacedwith the discontinuity in the discontinuous conduit 24 to complete theseries blood flow circuit 14. The module 26 contained all of thecomponents which were exposed to blood in the course of a treatment. Itincluded a conduit portion 28 which was placed in communication withsegments 30 of the discontinuous conduit 24 to complete the circuit 14.

The conduit portion 28 of the disposable module 26 had differentcomponents interposed therein. Blood was pumped from the egress point 16of cannulation at a vein to a heat exchanger 32 by means of a pump 34 ofappropriate construction. FIG. 2 illustrates the centrifugal pump 34that was used, but it will be understood that this specific type of pumpis not exclusive.

FIG. 2 illustrates a heat exchanger 32 down-flow from the pump 34. Theheat exchanger 32 functioned to selectively elevate the temperature ofthe blood to a desired level. The blood, after passing through the heatexchanger 32, passed through a perfusate filter 36. At this location,the perfusate can be purged of any impurities.

A flow probe or sensor 38 was in the series flow circuit 14 down-flowfrom the perfusate filter 36. The probe 38 served to sense informationwith regard to the measure of flow rate of the perfusate passing throughthe circuit 14. FIG. 2 illustrates the pressure transducer 40 that wasused in the circuit 14 down-flow from the flow sensor 38. While it isimportant to know flow rate of the perfusate through the circuit 14, itis also important to know the pressure through the system also.Consequently, the patient being treated can be adequately protected.

FIG. 2 also illustrates the temperature sensor 42 that was used in thecircuit 14. The sensor 42, of course, served to provide information withregard to the temperature of the blood flowing through the circuit 14.

FIG. 2 also shows a branch 44 of the circuit 14 which recirculatedexcess perfusate, not needed to be fed back into the patient, back tothe pump 34 for recirculation. The recirculation branch 44 was also usedduring initial setup.

Also illustrated are a series of tubing clamps 46. Such clamps 46 serve,basically, as occluders which can be disposed to pinch tubing segmentsto preclude flow therethrough. In FIG. 2, the three such tubing clamps46 that were used are illustrated. A first was immediately down-flow ofthe egress point on the patient. A second was located immediately priorto the location at which the blood reenters the patient's body. Thethird was positioned in the recirculation segment of the circuit 14.

FIG. 1 illustrates, as previously discussed, an integrated, sterilemodule 26 in which are disposed all of the components described withreference to FIG. 2 as being exposed to blood in the blood flow circuit14. FIG. 1 also, however, illustrates the non-disposable base unit thatwas used including a chassis 60 which removably mounts the integrated,sterile module 26. FIG. 1 further shows that the base unit included aconsole or controller unit 62 for controlling operation of thehyperthermia procedure being performed. The console 62 functioned toregulate and maintain perfusate flow rate, pressure, and temperature atdesired levels.

The console 62 had a series of digital display windows 64. Such windows64 read temperature, pressure, and flow rate and displayed thoseparameters for both actual sensed values and inputted alarm rangesettings. Each display 64 was provided with a series of visual alarms(i.e., LED's 66) for signaling when, for example, a desired range withinwhich temperature, flow rate, or pressure, is intended to be maintained,was exceeded. A series of alarm setting controls 68 were also shown asbeing provided. Each window 64 had corresponding upper and lower rangecontrols and an intermediately positioned toggle switch 70. The toggleswitch 70 could be toggled between positions representative of upper andlower range settings. When in an upper range setting, for example, theappropriate dial 72 could be maneuvered to adjust the upper range limit.

Finally, the control panel 74 of the console 62 had a lower row ofdials, displays, etc. These components included a timer 76, rate andamplitude controls 78 for additional modes of operation (such as apulsatile mode), and an electronic filter 80 for filtering aberrantamplitude signals regarding, for example, pressure in the circuit 14,etc.

In the structure illustrated in FIG. 1 and used to treat the patients,it is intended that the heater/cooler (not shown) for providing externalfluid to the heat exchanger 32 would not comprise part of the console62. Heat exchange was implemented in a collateral manner known in theprior art.

While not specifically shown in FIG. 1, the console 62 containedtherewithin a motor 82 which interfaces, through a wall, with theperfusate pump 34. This was done by providing the motor 82 with amagnetic rotor. As the motor 82 was driven, the rotor was caused to berotated also. A magnetic element was provided in the pump 34, and such amagnetic element interfaced, through the wall, with the magnetic rotor.Driving of the rotor, in turn, translated to operation of the pump 34 toa desired level.

FIG. 3 illustrates schematically how the pump 34, was controlled inresponse to pressure and flow rate levels sensed by respective sensors38, 40.

Those figures show the integrated, sterile module 26 and the componentsenclosed therewithin by a dotted line.

In utilizing the system for hyperthermia treatments, the patient wascannulated in the manner discussed above. Initially, the patient was outof the circuit 14, and flow bypassed the patient. This was effected bymanipulation of the appropriate tube clamps 46 to effect flow throughthe bypass branch circuit 44.

A selector switch 84 was manually positioned so that feedback wasprovided from either the motor 82, the pressure transducer 40, or theflow probe 38. Input from the appropriate feedback component passedthrough the selector switch 84 to a servo-amplifier 86. The amplifier86, in turn, inputted information to control the pump speed in anappropriate fashion to accomplish desired flow and pressure parameters.

FIG. 3 also illustrates a variable resistor 88 which was manipulated ininitiating the setting of a particular parameter. The parameter was setand, after the system was appropriately calibrated, the patient wasintroduced into the flow system 14. Thereafter, continuous monitoringwas performed of temperature, pressure, and flow rate. If the alarmsystem indicated that a parameter had gone outside the desired range,appropriate action was taken to bring the parameter back within therange.

During hyperthermia, pCO₂ varies directly with a change in bodytemperature. It is desirable to hold the bloods CO₂ content constantduring alpha-stat regulation, thereby requiring an inverse relationshipbetween air convection requirements and body temperature. Alpha-statmaintains constant CO₂ by regulating pCO₂. Hence, utilizing thealpha-stat technique for blood gas management is advantageous in thatthe pH gradient across the cellular membrane is preserved throughout therange of temperatures encountered during hyperthermia. This alpha-statregulation of blood pH and pCO₂ were used in treating the patients.

By direct control of pulmonary ventilation through manipulation ofrespiratory rate, the pCO₂, the total CO₂, and the pH were maintainedthroughout the procedure according to alpha-stat parameters, ensuringthat electrolyte balance was maintained throughout. No electrolytereplacement was required in any patient during the procedure, nor wasthere ever a need to administer sodium bicarbonate for metabolicacidosis.

The blood flow circuit comprised a Blood Gas Analyzer (BGA). Within theBGA is an analyzer which analyzes the blood gases, including the bloodpH and pCO₂ through infrared or chemical analysis. A pulse oximeterattached to the patient through suitable means, measured the PO₂ of apatient's blood. The microprocessor then analyzed the data associatedwith the blood's pH, pCO₂, PO₂ and calculated the base excess of theblood normalized at 37° C. The microprocessor was programmed to thenautomatically adjust the respiratory rate of the patient and either theamount of NaHCO₃ or acidotic crystalloid solution (which affects theHCO₃− ion concentration) being introduced into the patient's blood. Thiswas accomplished by adjusting the respiratory rate of the patientthrough ventilation or medications.

The respiratory management of the blood at constant CO₂ content, whilethe temperature was changed, maintained a constant alpha therebystabilizing the biochemical reactions fundamental to the metabolicwelfare of components of the patient's blood. The sodium bicarbonatebuffering system was based upon the following equation:

H⁺+HCO₃−˜H₂CO₃˜H₂O+CO₂

Acidosis (⇓pH) occurs when there is an increase of H+ (metabolic) and/orCO₂ (respiratory). Respiratory acidosis was treated with changes indepth of ventilation or ventilatory rate. Metabolic acidosis was treatedwith the administration of sodium bicarbonate (NaHCO₃). “Bicarb”dissociates into Na+ and HCO₃− which combines with H+ to form CO₂ andH₂O.

The blood gases, pH, PO₂, pCO₂, and HCO₃− concentration were obtained bydirect measurement. Base excess (BE) is a derived parameter based uponthe relationship between the measured pCO₂, and HCO₃− concentration, andis calculated relative to the normal HCO₃− centration values: 24 mEq/Lin arterial blood and 26 mEq/L in venous blood.

Optional Equipment That was not Used

A thermal sensor and bladder catheter that were not used to treat thepatients are described below.

Thermal Sensor

An improved temperature monitoring device suited to extracorporeal wholebody hyperthermia can be used.

The sensor described is connected to the blood flow circuit near thepatient. The temperature sensor has a very small mass and is place on astrut. The strut places the thermal sensor in the laminar blood flow ofa duct or fitting. In this fashion, a fast reacting thermal assessmentmay be made of blood temperature as blood enters or leaves the body.

FIG. 4 illustrates a temperature probe 133 for supporting thetemperature sensor 130 in the flow of blood moving through ahyperthermia system. As shown in FIG. 4, the probe 133 includes a tubeor flow-directing passage 140 having a wall defining an interior lumen141. Although a cylindrical shape is shown and is preferred to minimizewetted surface area, other cross-sectional shapes are operable. As shownin FIG. 4, the cross-sectional area of the lumen 141 remains constant inthe direction of flow indicated by arrow 138. It should be appreciatedthat the lumen 141 may decrease in cross-sectional area in the directionof flow to maintain laminar flow past the strut 134.

A temperature sensor 130 is attached to the strut 134. Preferably, thestrut 134 is shaped and positioned such that the sensor 30 supportedthereon is placed in a region of laminar flow and preferably near alocation of maximum flow velocity. A region of laminar flow isillustrated in the velocity profile 136. More specifically, the strut134 is shaped and positioned such that at least a portion of strut 134lies upstream of the site at which the strut 134 attaches to or passesthrough the tube 140. The preferred strut 134 has a generally arcuateshape along its length. As shown in the embodiment illustrated in FIG.4, the strut 134 has a terminating tip 145 that is positioned near theaxial center of the tube 140 where the blood flow achieves maximumvelocity. In this fashion the sensor 130 is located in the maximum flowzone in the device and can sense subtle changes in blood temperature. Bypositioning the sensor “in-line”, or in the flow of blood as it passesthrough the system, advantages are achieved. For example, the laminarflow prevents disruption of the blood and temperature change due tomixing. This factor combined with the fast response small thermal masssensor 130 improves control of body temperature.

The preferred form of the probe 133 includes fittings which may bebarbed. These allow the device to be positioned close to the patient. Itis believed that monitoring in close proximity to the patient isdesirable to minimize heat loss to the environment.

More than one sensor can be used in a hyperthermic system. The use of asecond sensor increases the ability of the system to accurately monitorand control temperature.

The sensors 130 and 132 may be of any temperature-sensing type, such asthermistors, thermocouples, and the like.

Bladder Catheter

An improved catheter can be used in the whole body hyperthermia system.In use, the catheter is suspended in the bladder of the patient. A cuffon the catheter inflates after the catheter is inserted in the bladderto assist in positioning and securing the catheter. The catheter has atemperature sensor proximal of the inflatable cuff to measure bodytemperature at the urinary sphincter muscle. The sensor is locatedrelative to the cuff a distance know to generally correspond to thetypical distance between the bladder and the sphincter muscle in humans.This distance is known to be approximately the same amongst humansregardless of size.

In an alternative catheter, a second temperature sensor is placed distalof the inflatable cuff and thus monitors the temperature of the urinepool in the bladder. Each of the measurements from the first and secondtemperature sensors has a different time constant depending on thevolume of urine in the bladder, and the level of perfusion in thesphincter. Data from these two sensors, the differences between thereadings, and the time-dependent variation of these two sensors cancontribute to the overall efficacy of the device.

An exemplary version of the bladder catheter is shown in the figures inwhich like reference numerals refer to equivalent structure throughout.

FIG. 5 shows a bladder temperature probe 230 having an elongate body 244and terminating in a proximal end 246 and further having a distal tip248 and a first temperature sensor 232, which may be of any conventionaltype, including thermistors, thermocouples or other solid statetemperature sensors. A drainage lumen 236 communicates with a distalopining 238 to allow fluid to be withdrawn from the bladder 231 or toallow fluid, such as saline, to be infused into the bladder. Aninflatable distal cuff 240 positions the catheter and prevents itsremoval from the bladder while the cuff is inflated. The sensor 232 andthe inflatable cuff are spaced and oriented such that when theinflatable cuff 240 holds the probe 230 in position in the patient'sbladder 231, the sensor 232 is located proximal of the urinary sphinctermuscle 242. Temperature information gathered at this site from thesurrounding tissue is likely to be reliable and somewhat less subject torapid fluctuation than a temperature reading taken from other locations,such as the urine pool.

In an alternate catheter, illustrated in FIG. 6, the catheter carries asecond temperature sensor 234. In practice, the cuff positions thesecond temperature sensor 234 in the bladder urine or fluid pool whilethe first sensor 232 is located adjacent the musculature near thesphincter 242. It is expected that the two sensors will vary in measuredtemperature as the effective time constants for the two locationsdiffer. These two temperatures and relative rates of their variationcontribute to the efficacy of body temperature control.

Computerized controls can be added to all of the equipment describedabove.

The above description is provided for the purpose of describingembodiments of the invention and is not intended to limit the scope ofthe invention in any way. It will be apparent to those skilled in theart that various modifications and variations can be made withoutdeparting from the spirit or scope of the invention. Thus, it isintended that the present invention cover the modifications andvariations of this invention provided they come within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A method for treating a patient infected with ahuman herpesvirus comprising raising the core temperature of the patientand then returning the core temperature of the patient to normal atleast one time, wherein the core temperature is raised to a temperaturerange and a duration sufficient to reduce the patient's viral load ofthe human herpesvirus by 30 percent or more one month after the coretemperature has been raised and returned to normal said at least onetime, and wherein the patient's viral load of the human herpesvirus isdetermined at least once after the core temperature has been raised andreturned to normal said at least one time.
 2. The method of claim 1,wherein the core temperature of the patient is raised and returned tonormal one time.
 3. The method of claim 1, wherein the core temperatureof the patient is raised and returned to normal two or more times. 4.The method of claim 1, wherein the core temperature is raised bycirculating the patient's blood from the patient, through anextracorporeal blood flow circuit, and back to the patient, wherein theblood returned to the patient has been heated within the blood flowcircuit to an elevated temperature range.
 5. The method of claim 1,wherein the core temperature is raised to a temperature range of from 38to 44° C.
 6. The method of claim 5, wherein the core temperature israised for a period of from 2 minutes to sixteen hours.
 7. The method ofclaim 5, wherein the core temperature is raised for a period of fromone-half to three hours.
 8. The method of claim 1, wherein the patient'sviral load of the human herpesvirus is determined at least once beforethe core temperature has been raised said at least one time.
 9. Themethod of claim 1, wherein the patient's viral load of the humanherpesvirus is reduced by 50 percent or more one month after the coretemperature has been raised and returned to normal said-at least onetime.
 10. The method of claim 1, wherein the patient's viral load of thehuman herpesvirus is reduced by 75 percent or more one month after thecore temperature has been raised and returned to normal said at leastone time.
 11. The method of claim 1, wherein the patient's viral load ofthe human herpesvirus is reduced by 90 percent or more one month afterthe core temperature has been raised and returned to normal said atleast one time.
 12. The method of claim 1, wherein the patient's viralload of the human herpesvirus is reduced by 95 percent or more one monthafter the core temperature has been raised and returned to normal saidat least one time.
 13. The method of claim 1, wherein the patient'sviral load of the human herpesvirus is reduced to less than thesensitivity level of a branched DNA signal amplification test one monthafter the core temperature has been raised and returned to normal saidat least one time.
 14. The method of claim 1, wherein the patient'sviral load of the human herpesvirus is reduced to less than thesensitivity level of a reverse transcriptase-polymerase chain reactiontest one month after the core temperature has been raised and returnedto normal said at least one time.
 15. The method of claim 1, furthercomprising treating the patient with a pharmaceutical indicated for thehuman herpesvirus.
 16. The method of claim 15, wherein thepharmaceutical is administered before raising the core temperature ofthe patient said at least one time.
 17. The method of claim 15, whereinthe pharmaceutical is administered while the core temperature of thepatient is raised.
 18. The method of claim 15, wherein thepharmaceutical is administered after the core temperature of the patienthas been raised and returned to normal said at least one time.
 19. Themethod of claim 15, wherein the pharmaceutical is selected frominterferons, protease inhibitors, cytokines, chemotherapeutic agents, orcombinations thereof.
 20. The method of claim 15, wherein thepharmaceutical is selected from ribavirin, lamivudine, interferonalfacon-1, interferon alfa-2a, interferon alfa-2b, interferon-alfa-n1,thymosin alpha-1, interleukin-2, interferon alpha-n3, ketoprofen,interferon beta-1a, interferon gamma-1b, interleukin-12, histaminedihydrochloride, thymalfasin, zidovudine, didanosine, zalcitabine,stavudine, abacavar, nevirapine, delaviridine, efavirenz, ritonavir,indinavir, nelfinavir, saquinavir, amprenavir, doxorubicin, aciclovir,cidofovir, famciclovir, foscarnet, ganciclovir, idoxuridine,trifluorothymidine, valaciclovir, vidarabine, or combinations thereof.21. The method of claim 15, wherein the pharmaceutical is selected froman interferon, ribavirin, lamivudine, or doxorubicin.
 22. The method ofclaim 15, wherein the pharmaceutical is an alpha interferon.
 23. Themethod of claim 15, wherein the pharmaceutical is doxorubicin.
 24. Themethod of claim 15, wherein the pharmaceutical is liposomal doxorubicin.25. The method of claim 1, wherein the patient has an acute humanherpesvirus infection.
 26. The method of claim 1, wherein the patienthas a latent human herpesvirus infection.
 27. The method of claim 1,wherein the patient is co-infected with a pathogen.
 28. The method ofclaim 27, wherein the pathogen is a virus.
 29. The method of claim 27,wherein the pathogen is a spirochete or bacterium.
 30. The method ofclaim 29, wherein the pathogen is a spirochete selected from the genustreponema, borrelia, or leptospira.
 31. The method of claim 29, whereinthe pathogen is a spirochete selected from Treponema pallidum, Treponemapertenue, Treponema carateum, Treponema pallidum endemicum, Borreliaburgdorferi, Borrelia hermsii, or Leptospira interrogans.
 32. The methodof claim 27, wherein the pathogen is a heat labile virus.
 33. The methodof claim 32, wherein the heat labile virus is selected fromhepadnaviruses, togaviruses, flaviviruses, coronaviruses, rhabdoviruses,filoviruses, paramyxoviruses, othomyxoviruses, bunyaviruses,arenaviruses, or retroviruses.
 34. The method of claim 32, wherein theheat labile virus is selected from HIV, hepatitis B virus, or hepatitisC virus.
 35. The method of claim 1, wherein the human herpesvirus isselected from human herpes virus-8, Epstein-Barr virus, humancytomegalovirus, varicella-zoster virus, herpes simplex virus-1, herpessimplex virus-2, human herpes virus-6, or human herpes virus-7.
 36. Themethod of claim 1, wherein the human herpesvirus is human herpesvirus-8.
 37. The method of claim 1, wherein the human herpesvirus isEpstein-Barr virus.
 38. The method of claim 1, wherein the humanherpesvirus is human cytomegalovirus.
 39. The method of claim 1, whereinthe human herpesvirus is varicella-zoster virus.
 40. The method of claim1, wherein the human herpesvirus is herpes simplex virus-1.
 41. Themethod of claim 1, wherein the human herpesvirus is herpes simplexvirus-2.
 42. The method of claim 1, wherein the human herpesvirus ishuman herpes virus-6.
 43. The method of claim 1, wherein the humanherpesvirus is human herpes virus-7.
 44. The method of claim 1, whereinthe herpesvirus is HHV-8, the patient has been receiving doxorubicin,and the patient still has progressive Kaposi's sarcoma prior to thetreating.
 45. A method for treating a patient infected with a humanherpesvirus comprising raising the core temperature of the patient andthen returning the core temperature of the patient to normal at leastone time, wherein the core temperature is raised to a temperature rangeand a duration sufficient to reduce the patient's viral load of thehuman herpesvirus by 30 percent or more three months after the coretemperature has been raised and returned to normal said at least onetime, and wherein the patient's viral load of the human herpesvirus isdetermined at least once after the core temperature has been raised andreturned to normal said at least one time.
 46. The method of claim 45,wherein the core temperature of the patient is raised and returned tonormal one time.
 47. The method of claim 45, wherein the coretemperature of the patient is raised and returned to normal two or moretimes.
 48. The method of claim 45, wherein the core temperature israised by circulating the patient's blood from the patient, through anextracorporeal blood flow circuit, and back to the patient, wherein theblood returned to the patient has been heated within the blood flowcircuit to an elevated temperature range.
 49. The method of claim 45,wherein the core temperature is raised to a temperature range of from 38to 44° C.
 50. The method of claim 49, wherein the core temperature israised for a period of from 2 minutes to sixteen hours.
 51. The methodof claim 49, wherein the core temperature is raised for a period of fromone-half to three hours.
 52. The method of claim 45, wherein thepatient's viral load of the human herpesvirus is determined at leastonce before the core temperature has been raised said at least one time.53. The method of claim 45, wherein the patient's viral load of thehuman herpesvirus is reduced by 50 percent or more three months afterthe core temperature has been raised and returned to normal said atleast one time.
 54. The method of claim 45, wherein the patient's viralload of the human herpesvirus is reduced by 75 percent or more threemonths after the core temperature has been raised and returned to normalsaid at least one time.
 55. The method of claim 45, wherein thepatient's viral load of the human herpesvirus is reduced by 90 percentor more three months after the core temperature has been raised andreturned to normal said at least one time.
 56. The method of claim 45,wherein the patient's viral load of the human herpesvirus is reduced by95 percent or more three months after the core temperature has beenraised and returned to normal said at least one time.
 57. The method ofclaim 45, wherein the patient's viral load of the human herpesvirus isreduced to less than the sensitivity level of a branched DNA signalamplification test three months after the core temperature has beenraised and returned to normal said at least one time.
 58. The method ofclaim 45, wherein the patient's viral load of the human herpesvirus isreduced to less than the sensitivity level of a reversetranscriptase-polymerase chain reaction test three months after the coretemperature has been raised and returned to normal said at least onetime.
 59. The method of claim 45, further comprising treating thepatient with a pharmaceutical indicated for the human herpesvirus. 60.The method of claim 59, wherein the pharmaceutical is administeredbefore raising the core temperature of the patient said at least onetime.
 61. The method of claim 59, wherein the pharmaceutical isadministered while the core temperature of the patient is raised. 62.The method of claim 59, wherein the pharmaceutical is administered afterthe core temperature of the patient has been raised and returned tonormal said at least one time.
 63. The method of claim 59, wherein thepharmaceutical is selected from interferons, protease inhibitors,cytokines, chemotherapeutic agents, or combinations thereof.
 64. Themethod of claim 59, wherein the pharmaceutical is selected fromribavirin, lamivudine, interferon alfacon-1, interferon alfa-2a,interferon alfa-2b, interferon-alfa-n1, thymosin alpha-1, interleukin-2,interferon alpha-n3, ketoprofen, interferon beta-1a, interferongamma-1b, interleukin- 12, histamine dihydrochloride, thymalfasin,zidovudine, didanosine, zalcitabine, stavudine, abacavar, nevirapine,delaviridine, efavirenz, ritonavir, indinavir, nelfinavir, saquinavir,amprenavir, doxorubicim, aciclovir, cidofovir, famciclovir, foscamet,ganciclovir, idoxuridine, trifluorothymidine, valaciclovir, vidarabine,or combinations thereof.
 65. The method of claim 59, wherein thepharmaceutical is selected from an interferon, ribavirin, lamivudine, ordoxorubicin.
 66. The method of claim 59, wherein the pharmaceutical isan alpha interferon.
 67. The method of claim 59, wherein thepharmaceutical is doxorubicin.
 68. The method of claim 59, wherein thepharmaceutical is liposomal doxorubicin.
 69. The method of claim 45,wherein the patient has an acute human herpesvirus infection.
 70. Themethod of claim 45, wherein the patient has a latent human herpesvirusinfection.
 71. The method of claim 45, wherein the patient isco-infected with a pathogen.
 72. The method of claim 71, wherein thepathogen is a virus.
 73. The method of claim 71, wherein the pathogen isa spirochete or bacterium.
 74. The method of claim 73, wherein thepathogen is a spirochete selected from the genus treponema, borrelia, orleptospira.
 75. The method of claim 73, wherein the pathogen is aspirochete selected from Treponema pallidum, Treponema pertenue,Treponema carateum, Treponema pallidum endemicum, Borrelia burgdorferi,Borrelia hermsii, or Leptospira interrogans.
 76. The method of claim 71,wherein the pathogen is a heat labile virus.
 77. The method of claim 76,wherein the heat labile virus is selected from hepadnaviruses,togaviruses, flaviviruses, coronaviruses, rhabdoviruses, filoviruses,paramyxoviruses, othomyxoviruses, bunyaviruses, arenaviruses, orretroviruses.
 78. The method of claim 76, wherein the heat labile virusis selected from HIV, hepatitis B virus, or hepatitis C virus.
 79. Themethod of claim 45, wherein the human herpesvirus is selected from humanherpes virus-8, Epstein-Barr virus, human cytomegalovirus,varicella-zoster virus, herpes simplex virus-1, herpes simplex virus-2,human herpes virus-6, or human herpes virus-7.
 80. The method of claim45, wherein the human herpesvirus is human herpes virus-8.
 81. Themethod of claim 45, wherein the human herpesvirus is Epstein-Barr virus.82. The method of claim 45, wherein the human herpesvirus is humancytomegalovirus.
 83. The method of claim 45, wherein the humanherpesvirus is varicella-zoster virus.
 84. The method of claim 45,wherein the human herpesvirus is herpes simplex virus-1.
 85. The methodof claim 45, wherein the human herpesvirus is herpes simplex virus-2.86. The method of claim 45, wherein the human herpesvirus is humanherpes virus-6.
 87. The method of claim 45, wherein the humanherpesvirus is human herpes virus-7.
 88. The method of claim 45, whereinthe herpesvirus is HHV-8, the patient has been receiving doxorubicin,and the patient still has progressive Kaposi's sarcoma prior to thetreating.